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- Genre: Academic theses
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Variability in subjective response to alcohol has been shown to predict drinking behavior as well as the development of alcohol use disorders. The current study examined the extent to which individual differences in alcohol pharmacokinetics impact subjective response and drinking behavior during a single session alcohol administration paradigm. Participants (N = 98) completed measures of subjective response at two time points following alcohol consumption. Pharmacokinetic properties (rate of absorption and metabolism) were inferred using multiple BAC readings to calculate the area under the curve during the ascending limb for absorption and descending limb for metabolism. Following the completion of the subjective response measures, an ad-libitum taste rating task was implemented in which participants were permitted to consume additional alcoholic beverages. The amount consumed during the taste rating task served as the primary outcome variable. Results of the study indicated that participants who metabolized alcohol more quickly maintained a greater level of subjective stimulation as blood alcohol levels declined and reported greater reductions in subjective sedation. Although metabolism did not have a direct influence on within session alcohol consumption, a faster metabolism did relate to increased ad-libitum consumption indirectly through greater acute tolerance to sedative effects and greater maintenance of stimulant effects. Rate of absorption did not significantly predict subjective response or within session drinking. The results of the study add clarity to theories of subjective response to alcohol, and suggest that those at highest risk for alcohol problems experience a more rapid reduction in sedation following alcohol consumption while simultaneously experiencing heightened levels of stimulation. Variability in pharmacokinetics, namely how quickly one metabolizes alcohol, may be an identifiable biomarker of subjective response and may be used to infer risk for alcohol problems.
ContributorsBoyd, Stephen (Author) / Corbin, William R. (Thesis advisor) / Chassin, Laurie (Committee member) / MacKinnon, David (Committee member) / Olive, Michael Foster (Committee member) / Arizona State University (Publisher)
Created2014
Description
Serotonin 1B receptor (5-HT1BR) agonists enhance cocaine intake in rats during daily self-administration (SA) sessions, yet decrease cocaine intake after prolonged abstinence. The goal of my dissertation was to examine if 5-HT1BRs are suitable targets for treatment development to attenuate psychostimulant intake. I first investigated if 5-HT1BR agonist effects that had been observed with cocaine generalize across psychostimulants, i.e., methamphetamine. Rats trained to self-administer methamphetamine received either CP 94,253 or the clinically-available but less selective 5-HT1D/1BR agonist, zolmitriptan, prior to tests for effects on SA both before and after a 21-day abstinence period. I found that CP 94,253 and zolmitriptan decreased the reinforcing and incentive motivational effects of methamphetamine, regardless of abstinence, unlike the pre-abstinence increase in cocaine SA observed previously with 5-HT1BR agonists. The attenuating effects of CP 94,253 on methamphetamine were antagonized in a 5-HT1BR-mediated manner. Subsequently, I investigated the efficacy and mechanism involved in effects of zolmitriptan on cocaine SA in male and female rats. Rats trained to self-administer cocaine received zolmitriptan prior to tests for effects on SA before a 21-day abstinence period. I found that zolmitriptan decreased cocaine intake in both sexes regardless of abstinence and without altering sucrose intake. I further demonstrated that the zolmitriptan effects on cocaine SA were mediated by both 5-HT1BRs and 5-HT1DRs. Finally, I examined if the abstinence-induced decrease in cocaine intake observed with the selective 5-HT1BR agonist, CP 94,253, persists during relapse after abstinence or reverts to enhancing cocaine intake, similar to effects observed without an abstinence period. Rats trained to self-administer cocaine resumed daily cocaine SA sessions after the forced abstinence period to investigate the effects of CP 94,253 on cocaine relapse. I found that CP 94,253 attenuated cocaine intake in relapse tests, suggesting that the abstinence-dependent attenuation of CP 94,253 on cocaine SA remains even after resumption of daily cocaine intake. The findings suggest that 5-HT1BR agonists like CP 94,253 and zolmitriptan have clinical potential as treatments for psychostimulant use disorders.
ContributorsGarcia, Raul (Author) / Neisewander, Janet L (Thesis advisor) / Olive, Michael Foster (Committee member) / Sanabria, Federico (Committee member) / Newbern, Jason M (Committee member) / Arizona State University (Publisher)
Created2020